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Effect of mutant TRP53 proteins on nutlin-3a treated mouse lymphoma cell lines (RNA-seq)

ABSTRACT: Mutations in TRP53, prevalent in human cancers, reportedly drive tumorigenesis through dominant-negative-effects (DNE) over wt TRP53 and neomorphic gain-of-function (GOF) effects. We show that five TRP53 mutants do not accelerate lymphomagenesis on a TRP53-deficient background but strongly synergize with c-MYC over-expression. RNA-seq analysis revealed that mutant TRP53 does not globally repress wt TRP53 function but exerts a DNE with disproportionate impact on subsets of wt TRP53 target genes, particularly those involved in DNA repair, proliferation and metabolism. This reveals that the mutant TRP53 DNE drives tumorigenesis by modulating wt TRP53 function in a manner that is advantageous for neoplastic transformation.

ORGANISM(S): Mus musculus

PROVIDER: GSE111950 | GEO | 2019/02/19

REPOSITORIES: GEO

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Transcriptome alterations in prostates from Trp53 R270H mutant mice following irradiation

Project description:Our group previously demonstrated that the Trp53 R270H mutation can drive prostate cancer (CaP) initiation in a genetically engineered mouse model (FVB.129S4(Trp53tm3Tyj/wt);FVB.129S(Nkx3-1tm3(cre)Mmswt)). The objective of the current study was to identify molecules that may facilitate Trp53 R270H-mediated prostate carcinogenesis. Mice that harbor a Trp53 R270H germline mutation (B6.129S4-Trp53tm3.1Tyj/J) were used for the current study. Wildtype (Trp53WT/WT), heterozygous (Trp53R270H/WT), and homozygous mice (Trp53R270H/R270H) were exposed to 5 Gy radiation to activate and stabilize p53 and thereby enhance our ability to identify differences in transcriptional activity between the 3 groups of mice. Mouse prostates were harvested 6 hours post-irradiation and either processed for histological/immunohistochemistry (IHC) analysis or snap-frozen for RNA extraction and transcriptome profiling with RNA-Sequencing (RNA-Seq) analysis. IHC was used to assess cell proliferation (Ki67) and apoptosis (activated caspase 3). PIN lesions were observed in heterozygous and homozygous mice as early as 3 months, thereby validating our prior finding that the Trp53 R270H mutation can drive CaP initiation. RNA-Seq analysis identified 1,378 differentially expressed genes, including multiple wildtype p53 target genes (E.g. Cdkn1a, Bax, Bcl2, Kras, Mdm2), p53 gain-of-function (GOF) genes (Mgmt, Id4), and CaP-related genes (Cav-1, Raf1, Kras). Our combined data validate a role for the Trp53 R270H mutation in CaP initiation, and identify molecules that may contribute to Trp53 R270H-mediated prostate carcinogenesis.

2022-03-02 | GSE130440 | GEO

Effects of TRP53 upregulation by nutlin 3a on the transcriptome of interstitial cell of Cajal (ICC) stem cells

Project description:Interstitial cells of Cajal (ICC) are electrical pacemakers and mediators of neuromuscular neurotransmission in the gastrointestinal tract. Studies in organotypic cultures of intact gastric muscular wall tissues identified Kit(low)Cd44(+)Cd34(+)Insr(+)Igf1r(+) cells as local ICC progenitors (Lorincz et al., Gastroenterology 2008;134:1083-1093). Subsequently, conditionally immortalized Kit(low)Cd34(+) cells were isolated by immunomagnetic and fluorescent cell sorting and serial cloning from the gastric muscular wall of homozygous, 14-day-old H-2Kb-tsA58 and 7-day-old wild-type C57BL/6J mice and shown to share other phenotypic characteristics with in-situ ICC precursors (Bardsley et al., Gastroenterology 2010;139:942-952). ICC and their precursors undergo age-related depletion in mice and humans. These changes are associated with increased protein levels for transformation-related protein 53 (TRP53). This study utilized total RNA-sequencing to investigate the effects of TRP53 upregulation by nutlin 3a treatment (control: nutlin 3b) on the transcriptome of the ICC precursor line D2211B maintained in the verified absence of the SV40 tsA58 large T antigen.

2020-08-24 | GSE139539 | GEO

NRF2 activation in TRP53:P16 deficient mice drives oral squamous cell carcinoma

Project description:NRF2 activation in TRP53:P16 deficient mice drives oral squamous cell carcinoma

2024-01-31 | PXD048887 | Pride

SMRT-seq of WT vs Trp53 MZ-KO eggs and embryos

Project description:Transcriptome of eggs and embryos from wt vs Trp53 KO

2021-05-21 | GSE149264 | GEO

Effect of mutant TRP53 proteins on nutlin-3a treated mouse lymphoma cell lines (RNA-seq)

Project description:Effect of mutant TRP53 proteins on nutlin-3a treated mouse lymphoma cell lines (RNA-seq)

| PRJNA438678 | ENA

RNAi off-target analysis in Trp53-/- mouse embryonic fibroblasts transduced with miRNA-based shRNAs targeting Trp53.

Project description:We analyzed miRNA-based shRNA off-target effects by transducing Trp53-/- MEFs at single- and high-copy with six well-characterized, potent and weak Trp53 shRNAs. To advance RNAi therapy for KRAS-mutant cancer, we developed a functionally validated library of siRNAs against RAS pathway genes that minimize off-target effects and enable combination gene silencing at low dose. We developed an in vivo model for real-time tracking of nanoparticle-based siRNA delivery and offer proof-of-principle that siRNA-mediated inhibition of a single gene (KRAS) or combinations of genes (A/B/C-RAF or KRAS+PIK3C-A/B) can impair the growth of KRAS-mutant colorectal cancer xenografts. Trp53-/- MEFs were transduced with LMP expressing Trp53 shRNAs at single copy (11-21% infection efficiency) and high copy (>98% infection efficiency), selected on puromycin and grown in absence of the selection agent before harvest. Uninfected Trp53-/- MEFs and Trp53-/- MEFs infected with an empty vector control served as M-bM-^@M-^\no shRNAM-bM-^@M-^] reference.

2014-08-01 | E-GEOD-59952 | biostudies-arrayexpress

Nutlin-3a selects for cells harbouring TP53 mutations.

Project description: Not available

| S-EPMC5215675 | biostudies-literature

Transcription profiling of wild type, Trp53-null and Trp53-515C/515C (encoding p53R172P) mouse embryo fibroblasts treated with gamma-radiation

Project description:Trp53-null, Trp53-515C/515C (encoding p53R172P), or wild-type mouse embryo fibroblasts were treated with 6 Gy gamma-radiation and harvested 6 hours later to compare expression profiles of genes regulated by wild-type p53 and p53R172P. Trp53-null cells were included as a negative control.

2006-11-20 | E-MEXP-917 | biostudies-arrayexpress

Wild Type Tumor Repressor Protein 53 (TRP53) Promotes Ovarian Cancer Cell survival

Project description:Loss of Pten in the KrasG12D;Amhr2-Cre mutant mice leads to the transformation of ovarian surface epithelial (OSE) cells and rapid development of low-grade, invasive serous adenocarcinomas. Tumors occur with 100% penetrance and express elevated expression of wild type tumor repressor protein 53 (TRP53). To test the functions of TRP53 in the Pten;Kras (Trp53+) mice, we disrupted the Trp53 gene yielding Pten;Kras(Trp53-) mice. By comparing morphology and gene expression profiles in the Trp53+ and Trp53- OSE cells, we document that wild-type TRP53 acts as a major promoter of OSE cell survival and differentiation: cells lacking Trp53 are transformed yet are less adherent, migratory and invasive and exhibit a gene expression profile more like normal OSE cells. These results provide a new paradigm: wild type TRP53 does not preferentially induce apoptotic or senescent related genes in the Pten;Kras(Trp53+) cancer cells but rather increases genes regulating DNA repair, cell cycle progression and proliferation and decreases putative tumor suppressor genes. However, if TRP53 activity is forced higher by exposure to nutlin-3a (an MDM2 antagonist), TRP53 suppresses DNA repair genes and induces the expression of genes that control cell cycle arrest and apoptosis. Thus, in the Pten;Kras(Trp53+) mutant mouse OSE cells and likely in human TP53+ low grade ovarian cancer cells, wild type TRP53 controls global molecular changes that are dependent on its activation status. These results suggest that activation of TP53 may provide a promising new therapy for managing type I ovarian cancer and other cancers in humans where wild-type TP53 is expressed. A direct comparison of ovarian surface epithelia cells from three different genotype mice

2012-06-20 | E-GEOD-34882 | biostudies-arrayexpress

Wild Type Tumor Repressor Protein 53 (TRP53) Promotes Ovarian Cancer Cell survival

2012-06-21 | GSE34882 | GEO

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